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Poly(I:C) enhances the susceptibility of leukemic cells to NK cell cytotoxicity and phagocytosis by DC.

Lion E, Anguille S, Berneman ZN, Smits EL, Van Tendeloo VF - PLoS ONE (2011)

Bottom Line: We previously reported that acute myeloid leukemic (AML) cells in response to electroporation with the synthetic dsRNA analogue poly(I:C) exert improved immunogenicity, demonstrated by enhanced DC-activating and NK cell interferon-γ-inducing capacities.Moreover, the enhanced killing and the improved uptake are strongly correlated.These data strongly support the use of poly(I:C) as a cancer vaccine component, providing a way to overcome immune evasion by leukemic cells.

View Article: PubMed Central - PubMed

Affiliation: Vaccine & Infectious Disease Institute (Vaxinfectio), Laboratory of Experimental Hematology, Faculty of Medicine, University of Antwerp, Antwerp, Belgium. eva.lion@ua.ac.be

ABSTRACT
α active specific immunotherapy aims at stimulating the host's immune system to recognize and eradicate malignant cells. The concomitant activation of dendritic cells (DC) and natural killer (NK) cells is an attractive modality for immune-based therapies. Inducing immunogenic cell death to facilitate tumor cell recognition and phagocytosis by neighbouring immune cells is of utmost importance for guiding the outcome of the immune response. We previously reported that acute myeloid leukemic (AML) cells in response to electroporation with the synthetic dsRNA analogue poly(I:C) exert improved immunogenicity, demonstrated by enhanced DC-activating and NK cell interferon-γ-inducing capacities. To further invigorate the potential of these immunogenic tumor cells, we explored their effect on the phagocytic and cytotoxic capacity of DC and NK cells, respectively. Using single-cell analysis, we assessed these functionalities in two- and three-party cocultures. Following poly(I:C) electroporation AML cells become highly susceptible to NK cell-mediated killing and phagocytosis by DC. Moreover, the enhanced killing and the improved uptake are strongly correlated. Interestingly, tumor cell killing, but not phagocytosis, is further enhanced in three-party cocultures provided that these tumor cells were upfront electroporated with poly(I:C). Altogether, poly(I:C)-electroporated AML cells potently activate DC and NK cell functions and stimulate NK-DC cross-talk in terms of tumor cell killing. These data strongly support the use of poly(I:C) as a cancer vaccine component, providing a way to overcome immune evasion by leukemic cells.

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Improved killing of K562 cells by NK cells in the presence of DC when K562 cells are sensitized with poly(I:C).Percentage killing of mock- and poly(I:C)-electroporated K562 cells by NK cells or by NK cells and DC. Cocultures were kept overnight at a 1∶1 NK:K562 or a 1∶1∶1 NK:DC:K562 cell ratio. Horizontal lines represent mean of 7 donors. Differences are statistically significant if p<0.05. Abbreviations: mock EP, electroporated without poly(I:C); pIC EP, electroporated with poly(I:C).
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pone-0020952-g004: Improved killing of K562 cells by NK cells in the presence of DC when K562 cells are sensitized with poly(I:C).Percentage killing of mock- and poly(I:C)-electroporated K562 cells by NK cells or by NK cells and DC. Cocultures were kept overnight at a 1∶1 NK:K562 or a 1∶1∶1 NK:DC:K562 cell ratio. Horizontal lines represent mean of 7 donors. Differences are statistically significant if p<0.05. Abbreviations: mock EP, electroporated without poly(I:C); pIC EP, electroporated with poly(I:C).

Mentions: cytokinesTo examine functional cross-talk between NK cells and DC, we simultaneously examined the killing and phagocytosis of AML cell lines in coculture with NK cells and autologous immature DC. Interestingly, the presence of DC in NK cell:K562 cell cocultures significantly improved tumor cell killing, provided that K562 cells were upfront electroporated with poly(I:C) (figure 4; p = 0.32 for mock-electroporated and p = 0.005 for poly(I:C)-electroporated K562 cells). This effect was not significant for U-937 (p = 0.15 for mock-electroporated and p = 0.46 for poly(I:C)-electroporated U-937 cells; data not shown). Next, we hypothesized that improved killing of poly(I:C)-electroporated tumor cells by NK cells could lead to an even higher uptake of apoptotic cells by DC. However, we could not see any improvement of phagocytosis of mock- nor poly(I:C)-electroporated tumor cells if NK cells were added to the coculture (p = 0.17 and p = 0.26 for K562 and p = 0.68 and p = 0.09 for U-937, respectively; data not shown).


Poly(I:C) enhances the susceptibility of leukemic cells to NK cell cytotoxicity and phagocytosis by DC.

Lion E, Anguille S, Berneman ZN, Smits EL, Van Tendeloo VF - PLoS ONE (2011)

Improved killing of K562 cells by NK cells in the presence of DC when K562 cells are sensitized with poly(I:C).Percentage killing of mock- and poly(I:C)-electroporated K562 cells by NK cells or by NK cells and DC. Cocultures were kept overnight at a 1∶1 NK:K562 or a 1∶1∶1 NK:DC:K562 cell ratio. Horizontal lines represent mean of 7 donors. Differences are statistically significant if p<0.05. Abbreviations: mock EP, electroporated without poly(I:C); pIC EP, electroporated with poly(I:C).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3117863&req=5

pone-0020952-g004: Improved killing of K562 cells by NK cells in the presence of DC when K562 cells are sensitized with poly(I:C).Percentage killing of mock- and poly(I:C)-electroporated K562 cells by NK cells or by NK cells and DC. Cocultures were kept overnight at a 1∶1 NK:K562 or a 1∶1∶1 NK:DC:K562 cell ratio. Horizontal lines represent mean of 7 donors. Differences are statistically significant if p<0.05. Abbreviations: mock EP, electroporated without poly(I:C); pIC EP, electroporated with poly(I:C).
Mentions: cytokinesTo examine functional cross-talk between NK cells and DC, we simultaneously examined the killing and phagocytosis of AML cell lines in coculture with NK cells and autologous immature DC. Interestingly, the presence of DC in NK cell:K562 cell cocultures significantly improved tumor cell killing, provided that K562 cells were upfront electroporated with poly(I:C) (figure 4; p = 0.32 for mock-electroporated and p = 0.005 for poly(I:C)-electroporated K562 cells). This effect was not significant for U-937 (p = 0.15 for mock-electroporated and p = 0.46 for poly(I:C)-electroporated U-937 cells; data not shown). Next, we hypothesized that improved killing of poly(I:C)-electroporated tumor cells by NK cells could lead to an even higher uptake of apoptotic cells by DC. However, we could not see any improvement of phagocytosis of mock- nor poly(I:C)-electroporated tumor cells if NK cells were added to the coculture (p = 0.17 and p = 0.26 for K562 and p = 0.68 and p = 0.09 for U-937, respectively; data not shown).

Bottom Line: We previously reported that acute myeloid leukemic (AML) cells in response to electroporation with the synthetic dsRNA analogue poly(I:C) exert improved immunogenicity, demonstrated by enhanced DC-activating and NK cell interferon-γ-inducing capacities.Moreover, the enhanced killing and the improved uptake are strongly correlated.These data strongly support the use of poly(I:C) as a cancer vaccine component, providing a way to overcome immune evasion by leukemic cells.

View Article: PubMed Central - PubMed

Affiliation: Vaccine & Infectious Disease Institute (Vaxinfectio), Laboratory of Experimental Hematology, Faculty of Medicine, University of Antwerp, Antwerp, Belgium. eva.lion@ua.ac.be

ABSTRACT
α active specific immunotherapy aims at stimulating the host's immune system to recognize and eradicate malignant cells. The concomitant activation of dendritic cells (DC) and natural killer (NK) cells is an attractive modality for immune-based therapies. Inducing immunogenic cell death to facilitate tumor cell recognition and phagocytosis by neighbouring immune cells is of utmost importance for guiding the outcome of the immune response. We previously reported that acute myeloid leukemic (AML) cells in response to electroporation with the synthetic dsRNA analogue poly(I:C) exert improved immunogenicity, demonstrated by enhanced DC-activating and NK cell interferon-γ-inducing capacities. To further invigorate the potential of these immunogenic tumor cells, we explored their effect on the phagocytic and cytotoxic capacity of DC and NK cells, respectively. Using single-cell analysis, we assessed these functionalities in two- and three-party cocultures. Following poly(I:C) electroporation AML cells become highly susceptible to NK cell-mediated killing and phagocytosis by DC. Moreover, the enhanced killing and the improved uptake are strongly correlated. Interestingly, tumor cell killing, but not phagocytosis, is further enhanced in three-party cocultures provided that these tumor cells were upfront electroporated with poly(I:C). Altogether, poly(I:C)-electroporated AML cells potently activate DC and NK cell functions and stimulate NK-DC cross-talk in terms of tumor cell killing. These data strongly support the use of poly(I:C) as a cancer vaccine component, providing a way to overcome immune evasion by leukemic cells.

Show MeSH
Related in: MedlinePlus